Improving detection of monogenic diabetes through reanalysis of GCK variants of uncertain significance.

Aims: To assess the utility of reanalysing GCK variants of uncertain significance (VUS) as an intervention to improve the detection of monogenic diabetes.

Methods: We examined GCK VUS in a local cohort of individuals with suspected monogenic diabetes and re-curated each variant against the recent ClinGen GCK-specific variant classification guidelines.

Results: Variant reanalysis achieved a new 'likely pathogenic' classification (i.e., positive results) in 4/8 identified VUS. The single most common newly applied criterion indicating variant pathogenicity was a confirmed phenotype of GCK-hyperglycaemia. RNA sequencing and segregation studies were performed in two cases but not additive to reclassification.

Conclusions: This is the first VUS reclassification study in monogenic diabetes using gene-specific guidelines. Within the limits of this small study, we observed a high rate (50%) of VUS upgrades to a positive result, thereby confirming the utility of VUS reanalysis- particularly with biochemical phenotyping- in increasing the detection of monogenic diabetes. We recommend HbA1c, fasting blood glucose and either pancreatic autoantibody negativity or a small oral glucose tolerance test increment as a feasible minimum dataset to inform variant classification at the individual patient level, noting the ongoing work of the ClinGen Monogenic Diabetes Expert Panel in systematically reviewing GCK variants at the international level.